Hydroxyphenyl-2-decahydroquinolylcarbinols

ABSTRACT

Hydroxyphenyl-2-decahydroquinolylcarbinols prepared by the condensation of an appropriately substituted ether derivative of a hydroxybenzaldehyde with 2-quinolyl lithium followed by removal of the ether group/s and reduction have Beta -adrenergic stimulant activity. Erythro and threo diastereoisomers may be conveniently separated.

United States Patent Kaiser [451 Sept. 12,1972

[ HYDROXYPHENYL-Z- OTHER PUBLICATIONS DECAHYDROQUINOLYLCARBINOLS [72] Inventor: Carl Kaiser, Haddon Heights, NJ. [73] Assignee: Smith Kline 8: French Laboratories,

Philadelphia, Pa.

[22] Filed: Nov. 23, 1970 [2|] Appl. No.: 92,161

[52] US. Cl. ..260/289 R, 260/268 R, 424/258 [SI] Int. Cl. ..C07d 33/02 [58] Field of Search ..260/289 R [56] References Cited UNITED STATES PATENTS 3,438,989 4/ I969 Shavel ..260/289 R Brown, Chem. Abstr., Vol. 44, C01. 2987- 8 1950) Primary Examiner-Donald G. Daus Attorney-William I-l. Edgerton, Richard D. Foggio, Joan S. Keps, Alan D. Lourie and Joseph A. Marlino [5 7] ABSTRACT l-lydroxyphenyl-Z-decahydroquinolylcarbinols prepared by the condensation of an appropriately substituted ether derivative of a hydroxybenzaldehyde with 2-quinolyl lithium followed by removal of the ether group/s and reduction have Badrenergic stimulant activity. Erythro and threo diastereoisomers may be conveniently separated.

8 Claims, No Drawings HYDROXYPHENYL-Z- DECAHYDROQUINOLYLCARBINOLS This invention relates to novel hydroxyphenyl-L decahydroquinolylcarbinols which have useful pharmacodynamic activity. More specifically the com measure of B-stimulant (direct relaxant) effect on airway smooth muscle, and (2) effect on rate of spontaneously beating right atria of the guinea pig as a measure of. [S -stimulant effect on cardiac muscle. .The compounds of this invention have selective bronchodilating properties since theyare active in (i) above at a doselower than is required in tive separation ratio. f r p The compounds of this invention are represented by the following generalstructural formula: Y

( 2) above resulting in a posi- 4 I'IN FORMULAI inwhichr 7 v R represents hydrogen, methyl or chlorine; and

R represents hydroxy in the 4 or 5 position.

Advantageous compounds of formula I are those wherein R, is hydrogen and R2 is hydroxy in the 4 or 5 position. 1

The compounds of this invention may be used in the form of a pharmaceutically acceptable acid addition salt having the utility of the free base. Such salts, prepared by methods well known to the art, are formed with both inorganic or organic acids,- for example: maleic, fumaric, benzoic, ascorbic, pamoic, succinic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, paminobenzoic, glutamic, benzenesulfonic, hydrochloric, hydrobromic, sulfuric, cyclohexyl sulfamic, phosphoric and nitric acids.

Further-the compoundsof this invention may be present as diastereoisomers and are designated as erythroand threo-isomers which may be resolved as d, 1 optical isomers. Due to the presence of the decahydroquinoline ring, the compounds may also exist as cis' and trans isomers. Unless otherwise specified in the description and accompanying claims, it is intended to include all isomers, whether separated or mixtures thereof.

A preferred compound of this invention is erythro- 3,4-dihydroxyphenyl-Z-decahydroquinolylcarbinol which relaxes the spontaneous tone of guinea pig tracheal ring preparation at an ED of 0.28 mcg./ml. whileincreasing the rate of contraction of guinea pig right atria at an ED of 5.0 meg/ml. These activities give an absolute separation ratio of-18 which is a 36 fold improvement when compared to-the corresponding activity of d, 1 isoproterenol (absolute separation ratio 0.5) in similar in vitro preparations.

The compounds of this invention are prepared from a sequence of reactions illustrated by the following preparation of 3,4-dihydroxyphenyl-2-decahydroquinolylcarbinol:

Thus, as shown above, a lower alkyl ether derivative of an appropriately substituted hydroxybenzaldehyde is condensed with a 2-haloquinoline, preferably bromo, in the presence of an organometal derivative, preferably butyl lithium, and in an organic nonreactive solvent such as tetrahydrofuran or ether to give a substituted phenyl 2-quinolylcarbinol. The latter is oxidized forexample with potassium permanganate to the corresponding ketone. The 'ketone is demethylated with 48 percent hydrobromic acid and then reduced with for example platinum oxide and hydrogen to give the hydroxyphenyl-Z-decahydroquinolylcarbinol. This results in a mixture of erythro/threo isomers present in about a 4:1 ratio. The individual isomers are obtained by fractional crystallization of the product, preferably as an acid addition salt.

Alternatively a benzyl ether derivative of an appropriately substituted hydroxybenzaldehyde is condensed as above with a 2-haloquinoline to give a substituted phenyl- 2-quinolylcarbinol. The latter is reduced with platinum oxide and hydrogen to give the formula I may be separated, for example, by the following procedure. The benzyl ether derivative of an appropriately substituted hydroxybenzaldehyde is treated as described above with 2-quinolyl lithium and the resulting quinolylc'arbinol as the hydrochloride is reduced catalytically to give an isomeric mixture of benzyloxyphenyl-Z-decahydroquinolylcarbinol hydrochlorides from which a single hydrochloride is isolated by recrystallization. The latter is converted to its diastereoisomer by thionyl chloride conversion to the chloride (retention) followed by hydrolysis of the chloride with aqueous silver nitrate (inversion). Stereochemistry of the diastereoisomers is established by examination of the n.m.r. spectra of the correspondmg cyclic carbamates derived from treatment with phosgene. Debenzylation of the separated benzyloxyphenyl-2-decahydroquinolylcarbinol diastereoisomers as described above affords the erythro and threo products of formula I.

The compounds of this invention may be administered orally or parenterally in conventional dosage unit forms such as tablets, capsules, injectables or the like, by incorporating the appropriate dose of a compound of formula I, with carriers according to accepted pharmaceutical practices. Preferably a compound or an acid addition salt thereof is administered orally to an animal organism in a tablet or capsule comprising an amount sufficient to produce B-adrenergic stimulant activity. Each dosage unit will contain the active medicament in an amount of about 25 mg. to about 50 mg. Advantageously equal doses will be administered threeto four times daily with the daily dosage regimen being about 75 mg. to about 200 mg.

The pharmaceutical carrier employed may be, for example, either a solid or liquid. Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary of liquid carriers are syrup, pe-

anut oil, olive oil, water and the like. Similarly the carrier or diluent can include any time delay material well known to the art, such as glyceryl monostearate or lozenge. The amount of solid carrierwill vary widely but preferably will be about 25 mg. to about 1 g. If a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile bility for intranasal administration is an aerosol dispensing system wherein the active medicament is incorporated with Freon or other inert propellant in an aerosol container. Such an aerosol system will deliver a metered dose of about 250 mcg. to about 500 mcg., administered once or twice at a time as needed. Also useful for this purpose is a liquid formulation in a plastic squeeze bottle.

The foregoing is a general description of how to prepare the compounds of this invention. The following examples illustrate the preparation of specific compounds having B-adrenergic stimulant activity. However, this should not be construed as a limitation of the invention since appropriate variations in the starting materials will produce other products set forth hereinabove.

EXAMPLE 1 A stirred solution of 56.3 ml. of 1.6 M solution of butyl lithium in hexane is cooled to 40C. under nitrogen and 15.9 g. (0.0765 m.) of 2-bromoquinoline in 30 ml. of ether is added dropwise. The mixture is stirred 15 minutes at -40 C. and a solution of 12.7 g. (0.0765 m.) of 3,4-dimethoxybenzaldehyde in 60 ml. of ether is added. After stirring at 15 C. for minutes, the mixture is poured into 150 g. ice/100 ml. concentrated hydrochloric acid. The separated aqueous layer is made alkaline with concentrated ammonium hydroxide, extracted with ether and the dried extract concentrated to give 3,4-dimethoxyphenyl-2- quinolylcarbinol as an orange gum.

A stirred suspension of 18.9 g. (0.05 m.) of the above carbinol in 300 ml. of water is heated to 70C. and 15.2 g. (0.0963 m.) of potassium permanganate is added in portions. The mixture is stirred and heated on a steam bath for 40 minutes, cooled to 30C. and diluted with 300 ml. of ethyl acetate. This mixture is filtered, and the organic extract is dried and concentrated to give 3,4-dimethoxyphenyl-2-quinolyl ketone, m.p. l0l-l0 3C.

- A solution of 6.9 g. of the above ketone in 200 ml. of 48 percent hydrobromic acid is refluxed for one and one-half hours and then concentrated in vacuo. The residue is dissolved in ethanol, toluene is added, the solution concentrated and the residue stripped with toluene to yield 3,4-dihydroxyphenyl-2-q uinolyl ketone hydrobromide, m.p. 228234 C.

. The hydrobromide is triturated with ml. of sodium bicarbonate solution and extracted with ethyl acetate. The product is evaporated and the residue recrystallized from acetonitrile to yield the'free base having a melting point of 20l-202 C.

The free base is treated with a mixture of acetonehydrochloric acid-ether to yield the 3,4-dihydroxyphenyl-2-quinolyl ketone hydrochloride, m.p. 2 l 9-227 C. c

A mixture of 0.5 g. of plantinum oxide and a solution of 3.4 g. (0.0113 m.) of 3,4-dihydroxyphenyl-2-quinolyl ketone hydrochloride in 20 ml. of water and ml. of ethanol is hydrogenated on the Parr apparatus using an initial hydrogen pressure of 50 psi at room temperainjectable liquid such as an ampule, or. an aqueous or nonaqueous liquid suspension. Of "particular applicature. The reaction mixture is filtered, the filtrate concentrated in vacuo. The residue is recrystallized from methanol-ether to give erythro-3',4-dihydroxy-phenyl- 2-decahydroquinolylcarbinol hydrochloride, m.p. 2'l6-2l7C. (decomp.).' I

EXAMPLE 2 Condensation of 20.8 g. of 3,5-dimethoxybenzaldehyde with quinolyl lithium (from 19.8 g. of 2- bromoquinoline and 64 ml. of 1.6 M of butyl lithium in hexane) is carried'out as in Example 1 to give 3,5- dimethoxyphenyl-2-quinolylcarbinol. Oxidation of the carbinol with potassium permanganate gives 3,5- dimethoxyphenyl-Z-quinolyl ketone. A solution of the ketone (7.5 g.) and 65 ml. of 48percent hydrobromic acid is refluxed for two hours, concentrated in vacuo and the residue crystallized to yield 3,5-dihydroxyphehyl-2-quinolyl. ketone hydrobromide. The latter (3.8 g.) in 100 ml. of methanol is hydrogenated in a Parr apparatus at 25C. and an initial hydrogen pressure of 60 psi. in the presence of 0.9 g. of platinum oxide. The'reaction mixture is filtered and the filtrate concentrated to give". 3,5-dihydroxyphenyl-2- decahydroquinolylcarbinol-hydrobromide.

' Tr'eatment'of the hydrobromide with'aqueous sodium bicarbonate followed by .extraction with ethyl acetate yields the free base of the carbinolwhich may be reacted with other acids as described hereinabove to give other acid addition salts.

EXAMPLE3 I To a stirred solution of 25 g. (0.134 m.) of 2- chloroisovanillin in 80ml. of methylene chloride at 0 1 trated and diluted with water to give 2-chloro-3,4-

dibenzyloxybenzaldehyde.

Condensation of 6.65 g. (0.0189 m.) of the above aldehyde with quinolyl lithium (from 3.0 g. of 2- bromoquinoline and 9.8 ml. of 1.6 M butyl lithium in hexane) yields 2-chloro-3,4-dibenzyloxyphenyl-2-quinolylcarbinol.

A mixture of 2.85 g. (0.0061 rn.) of the above hydrochloride, 0.7 g. of platinum oxide and 100 ml. of methanol is hydrogenated at 25C. and on initial hydrogen pressure of 60 psi on a Parr apparatus. After 45 minutes the reaction mixture is filtered, the filtrate concentrated and the residue crystallized to give 2- chloro-3,4-dibenzyloxyphenyl-2-decahydroquinolylcarbinol hydrochloride.

The above dibenzyloxy derivative (2.3 g.) with 0.6 g. of 10 percent palladiumon-carbon in 100 ml. of methanol is hydrogenated on a Parr apparatus at 25C. and 60 psi initial hydrogen pressure. After minutes the reaction mixture is filtered, the filtrate concentrated and the residue triturated with acetone to give 2- chloro-3,4-dihydroxyphenyl-Z-decahydroquinolylcarbinol hydrochloride.

EXAMPLE 4 Following the procedure of Example 1, a solution of 10.9 g. (0.0523 rn.) of 2-bromoquinoline in 45 ml. of ether is added dropwise to a stirred solution of 40 ml. of

1.6 M butyl lithium in hexane cooled to 40C. A solution of 9.42 g. (0.0523 m.) of 2-methyl-3,4-dimethoxybenzaldehyde in 45 ml. of ether is added. After stirring at 15C. for 45 minutes, the reaction mixture is poured into ice/concentrated hydrochloric acid to yield after similar workup 3,4-dimethoxy-2-methylphenyl-Z- quinolylcarbinol. Oxidation of the carbinol, 7.3 g. (0.0282 rn.), with 1.5 equivalents of potassium permanganate in ml. of water gives 3,4-dimethoxy-2 methylphenyl-2-quinolyl ketone.

A solution of 5 g. (0.0194 m.) of the ketone in 50 ml. of 48 percent hydrobromic acid is refluxed with stirring for one and one-half hours, evaporated in vacuo and the residue crystallized to give 4-hydroxy-3-methoxy-2- methylphenyl-Z-quinolyl ketone hydrobromide. The latter (2.67'g.) is refluxed in ml. of 48 percent hydrobromic acid for 2 hours and similarly worked up to furnish the 3,4-dihydroxy-2-methylphenyl-2-quinolyl ket'o'ne hydrobromide.

To a solution of 2.2 g. (0.0071 m.) of 3,4- dihydroxy- 2-methylphenyl-2-quinolyl ketone hydrobromide in 20 ml. of water and 80 ml. of methanol is added 0.3g. of platinum oxide. The mixture is hydrogenated on the Parr apparatus using an initial hydrogen pressure of 60 psi at 25C. Hydrogen uptake is complete in about 15 minutes and the reaction mixture is filtered. The filtrate is treated with sulfur dioxide, concentrated in vacuo and the residue crystallized to yield 3,4-dihydroxy-2- methylphenyl-2-decahydro-quinolylcarbinol hydrobromide. The hydrobromide (0.8 g.) in about 5 ml. of water is neutralized with potassium carbonate. The free base thus obtained is suspended in methanol and ethereal hydrogen chloride is added to give the corresponding decahydroquinolylcarbinol hydrochloride.

What is claimed is:

1. A chemical compound of the formula:

. l H X/ which R is hydroxy in the 5 position being the compound 3,5dihydroxyphenyl-2-decahydroquinolylcarbinol.

3,4-dihydroxy-2-methylphenyl-2- 7. A chemical compound according to claim 1 in which R is chlorine and R is hydroxy in the 4 position being the compound 2-chloro-3,4-dihydroxyphenyl-2- decahydroquinolylcarbinol.

8. A chemical compound according to claim 1 in 5 which R is methyl and R is hydroxy in the 4 position being the compound 3,4-dihydroxy-Z-methylphenyl-2- decahydroquinolylcarbinol. 

2. A chemical compound according to claim 1 in which R1 is hydrogen.
 3. A chemical compound according to claim 2 in which R2 is hydroxy in the 4 position being the compound 3,4-dihydroxphenyl-2-decahydroquinolylcarbinol.
 4. The erythro diastereoisomer of the compound according to claim
 3. 5. The threo diastereoisomer of the compound according to claim
 3. 6. A chemical compound according to claim 2 in which R2 is hydroxy in the 5 position being the compound 3,5-dihydroxyphenyl-2-decahydroquinolylcarbinol.
 7. A chemical compound according to claim 1 in which R1 is chlorine and R2 is hydroxy in the 4 position being the compound 2-chloro-3,4-dihydroxyphenyl-2-decahydroquinolylcarbinol.
 8. A chemical compound according to claim 1 in which R1 is methyl and R2 is hydroxy in the 4 position being the compound 3, 4-dihydroxy-2-methylphenyl-2-decahydroquinolylcarbinol. 